Prevalence of copy number variants (CNVs) and rhGH treatment efficacy in an Italian cohort of children born small for gestational age (SGA) with persistent short stature associated with a complex clinical phenotype.

PURPOSE: Multiple factors influence intrauterine growth and lead to low birth sizes. The impact of genetic alterations on both pre- and post-natal growth is still largely unknown. The aim of this study was to investigate the prevalence of CNVs in an Italian cohort of SGA children with persistent short stature and complex clinical phenotype. rhGH treatment efficacy was evaluated according to the different genotypes. SUBJECTS AND METHODS: Twenty-four SGA children (10F/14M) with persistent short stature associated with dysmorphic features and/or developmental delay underwent CNV evaluation. RESULTS: CNVs were present in 14/24 (58%) SGA children. Six patients had a microdeletion involving the following regions: 3q24q25.1, 8p21.2p12, 15q26, 19q13.11, 20q11.21q12, 22q11.2. In three females, the same microdeletion involving 17p13.3 region was identified. In two different patients, two microduplications involving 10q21.3 and Xp11.3 region were observed. A further female patient showed both an 11q12.1 and an Xq27.1 microduplication, inherited from her mother and from her father, respectively. In a boy, the presence of a 12p13.33 microdeletion and a 19q13.43 microduplication was found. GH treatment efficacy, expressed by height gain and height velocity in the first 12 months of therapy, was similar in subjects with and without CNVs. CONCLUSIONS: These results show that pathogenic CNVs are common in SGA children with short stature associated with additional clinical features. Interestingly, the involvement of 17p13.3 region occurs with a relative high frequency, suggesting that genes located in this region could play a key role in pre- and post-natal growth. rhGH therapy has similar efficacy in the short term whether CNVs are present or not.

Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease.

CONTEXT: Growth hormone (GH) and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: To assess relationships between hepatic expression of IGF1 and IGF-binding proteins (IGFBPs) and measures of glycemia and liver disease in adults with NAFLD. Secondarily to assess effects of GH-releasing hormone (GHRH) on circulating IGFBPs. DESIGN: Analysis of data from a randomized clinical trial of GHRH. SETTING: Two US academic medical centers. PARTICIPANTS: Participants were 61 men and women 18 to 70 years of age with HIV-infection, ≥5% hepatic fat fraction, including 39 with RNA-Seq data from liver biopsy. MAIN OUTCOME MEASURES: Hepatic steatosis, inflammation, and fibrosis by histopathology and measures of glucose homeostasis. RESULTS: Hepatic IGF1 mRNA was significantly lower in individuals with higher steatosis and NAFLD Activity Score (NAS) and was inversely related to glucose parameters, independent of circulating IGF-1. Among the IGFBPs, IGFBP2 and IGFBP4 were lower and IGFBP6 and IGFBP7 (also known as IGFBP-related protein 1) were higher with increasing steatosis. Hepatic IGFBP6 and IGFBP7 mRNA levels were positively associated with NAS. IGFBP7 mRNA increased with increasing fibrosis. Hepatic IGFBP1 mRNA was inversely associated with glycemia and insulin resistance, with opposite relationships present for IGFBP3 and IGFBP7. GHRH increased circulating IGFBP-1 and IGFBP-3, but decreased IGFBP-2 and IGFBP-6. CONCLUSIONS: These data demonstrate novel relationships of IGF-1 and IGFBPs with NAFLD severity and glucose control, with divergent roles seen for different IGFBPs. Moreover, the data provide new information on the complex effects of GHRH on IGFBPs.

Growth hormone-releasing hormone promotes therapeutic effects of peripheral blood endothelial progenitor cells in ischemic repair.

PURPOSE: In peripheral artery disease, blockage of the blood supply to the limbs leads to blood flow attenuation and tissue ischemia. We investigated whether growth hormone-releasing hormone (GHRH) could enhance the biological functions and therapeutic effects of endothelial progenitor cells (EPCs) derived from adult human peripheral blood (PB). METHODS: EPCs were isolated from human PB (PB-EPCs) and cord blood and expanded in vitro. PB-EPCs incubated with or without GHRH were evaluated for proliferation, migration, and angiogenesis capacity and apoptosis rates under oxidative stress conditions. Activation of STAT3 and Akt pathways was evaluated using Western blot. A hind-limb ischemia (HLI) mouse model was used to study the efficacy of GHRH in improving EPC therapy in vivo. RESULTS: GHRH enhanced the proliferation, migration, and angiogenesis capacity of PB-EPCs and reduced apoptosis under H2O2 stimulation. These beneficial effects were GHRH receptor-dependent and were paralleled by increased phosphorylation of STAT3 and Akt. Transplantation of GHRH-preconditioned EPCs into HLI model mice enhanced blood flow recovery by increasing vascular formation density and enhanced tissue regeneration at the lesion site. CONCLUSION: Our studies demonstrate a novel role for GHRH in dramatically improving therapeutic angiogenesis in HLI by enhancing the biological functions of EPCs. These findings support additional studies to explore the full potential of GHRH in augmenting cell therapy for the management of ischemia.

Anabolic and anticatabolic agents used in burn care: What is known and what is yet to be learned.

Major thermal injury induces profound metabolic derangements secondary to an inflammatory "stress-induced" hormonal environment. Several pharmacological interventions have been tested in an effort to halt the hypermetabolic response to severe burns. Insulin, insulin growth factor 1, insulin growth factor binding protein 3, metformin, human growth hormone, thyroid hormones, testosterone, oxandrolone, and propranolol, among others, have been proposed to have anabolic or anticatabolic effects. The aim of this broad analysis of pharmacological interventions was to raise awareness of treatment options and to help establishing directions for future clinical research efforts. A PubMed search was conducted on the anabolic and anticatabolic agents used in burn care. One hundred and thirty-five human studies published between 1999 and 2017 were included in this review. The pharmacological properties, rationale for the treatments, efficacy considerations and side effect profiles are summarized in the article. Many of the drugs tested for investigational purposes in the severely thermally injured are not yet gold-standard therapies in spite of their potential benefit. Propranolol and oxandrolone have shown great promise but further evidence is still needed to clarify their potential use for anabolic and anticatabolic purposes.

Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people with HIV and there are no proven pharmacological treatments for the disease in this population. We assessed the effects of tesamorelin on liver fat and histology in people with HIV and NAFLD. METHODS: This randomised, double-blind, multicentre study with identical placebo as a comparator was done in a hospital and a medical research centre in the USA. People with HIV infection and a hepatic fat fraction (HFF) of 5% or more by proton magnetic resonance spectroscopy were eligible. Participants were randomly assigned (1:1) to receive either tesamorelin 2 mg once daily or placebo once daily for 12 months, followed by a 6-month open-label phase during which all participants received tesamorelin 2 mg daily. The randomisation list was prepared by the study statistician using a permuted block algorithm within each stratum with randomly varying block sizes. The primary endpoint was change in HFF between baseline and 12 months. The primary safety endpoint was glucose. Analysis was by intention to treat using all available data. This trial is registered with ClinicalTrials.gov, number NCT02196831. FINDINGS: 61 patients were enrolled between Aug 20, 2015, and Jan 16, 2019, of whom 30 received tesamorelin and 30 received placebo. Patients receiving tesamorelin had a greater reduction of HFF than did patients receiving placebo, with an absolute effect size of -4·1% (95% CI -7·6 to -0·7, p=0·018), corresponding to a -37% (95% CI -67 to -7, p=0·016) relative reduction from baseline. After 12 months, 35% of individuals receiving tesamorelin and 4% receiving placebo had a HFF of less than 5% (p=0·0069). Changes in fasting glucose and glycated haemoglobin were not different between groups at 12 months. Individuals in the tesamorelin group experienced more localised injection site complaints than those in the placebo group, though none were judged to be serious. INTERPRETATION: Tesamorelin might be beneficial in people with HIV and NAFLD. Further studies are needed to determine the long-term effects of tesamorelin on liver histology. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.

Growth Hormone-Releasing Hormone Modulation of Neuronal Exosome Biomarkers in Mild Cognitive Impairment.

Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aß1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aß1-42, neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients.

[Observation on clinical effects of recombinant human growth hormone on the treatment of children with severe burn].

Objective: To observe the clinical effects of recombinant human growth hormone (rhGH) on children with severe burn. Methods: Clinical data of 94 children with severe burn, hospitalized in our burn unit from April 2012 to December 2016, conforming to the study criteria, were retrospectively analyzed. According to the use of rhGH, children were divided into rhGH group (n=50) and control group (n=44). Children in control group received conventional treatment, while children in rhGH group received both conventional and rhGH treatment. The rhGH treatment was started 3 to 5 days post injury in dosage of 0.2-0.4 U·kg(-1)·d(-1,) by way of subcutaneous injection, and the course of treatment was (11±5) d. The plasma albumin and prealbumin levels, heart rate, alanine aminotransferase (ALT), and serum creatinine level in 2 weeks post injury, times of skin grafting operation, hospitalization time, total hospitalization treatment cost, and sepsis and death of children were compared between the 2 groups. Data were processed with independent sample t test, Mann-Whitney U test, and Fisher's exact test. Results: (1) In 2 weeks post injury, the plasma albumin level [(36±4) g/L] and prealbumin level [(94±34) g/L] of children in rhGH group were significantly higher than those in control group [(33±4) and (73±20) g/L, t=3.666, 3.401, P<0.05]. (2) In 2 weeks post injury, the heart rate of children in rhGH group was (123±11) times per minute, which was slower than (130±14) times per minute of children in control group (t=2.839, P<0.05). There was no significant difference in ALT level of children between the 2 groups (Z=0.868, P>0.05). The blood creatinine levels of children in the 2 groups were within normal range. (3) The times of skin grafting operation of children in rhGH group was 0.3±0.5, which was significantly less than 0.5±0.6 in control group (Z=2.234, P<0.05). The hospitalization time of children in rhGH group was (22±8) days, which was shorter than (28±10) days in control group (t=2.837, P<0.05). The total hospitalization treatment cost of children in rhGH group was (41±15) thousand yuan, which was significantly less than (53±25) thousand yuan in control group (t=2.878, P<0.05). (4) There were 2 cases of sepsis in control group and 1 case of sepsis in rhGH group, with no significant difference between the 2 groups (P>0.05). No children died in the 2 groups. Conclusions: rhGH treatment of children with severe burn can correct post-injury hypoproteinemia, improve cardiac function, reduce the times of skin grafting operation and hospitalization treatment cost, shorten hospitalization time, with no significant effect on kidney and liver function, sepsis, and death.

Cardiovascular risk and dyslipidemia among persons living with HIV: a review.

BACKGROUND: Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles? DISCUSSION: Prevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments. Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted. Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied. Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered. Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin. Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice. CONCLUSIONS: Cardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients.

Visceral fat reduction with tesamorelin is associated with improved liver enzymes in HIV.

OBJECTIVE: Tesamorelin reduces visceral adipose tissue (VAT) in HIV. We investigated whether reductions in VAT with tesamorelin are associated with changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). DESIGN AND METHODS: We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity. These studies showed that the majority of patients treated with tesamorelin are 'responders', defined a priori by the Food and Drug Administration as achieving at least 8% reduction in VAT. In the current analysis, we sought to examine the impact of VAT reduction on ALT and AST among patients participating in the Phase III trials with baseline elevated ALT or AST. Within this group, we compared changes in ALT and AST in VAT responders vs. nonresponders after 26 weeks of treatment, and then assessed the effects of drug discontinuation on these endpoints over a subsequent 26-week period. RESULTS: At baseline, VAT was positively associated with ALT (P = 0.01). In study participants assigned to tesamorelin with baseline ALT or AST more than 30 U/l, VAT responders experienced greater reductions in ALT (-8.9 ±â€Š22.6 vs. 1.4 ±â€Š34.7 U/l, P = 0.004) and AST (-3.8 ±â€Š12.9 vs. 0.4 ±â€Š22.4 U/l, P = 0.04) compared with nonresponders over 26 weeks. This improvement among VAT responders persisted over 52 weeks even in those switched to placebo despite a partial reaccumulation of VAT. CONCLUSION: A clinically significant VAT reduction with tesamorelin was associated with improved liver enzymes among HIV-infected patients with abdominal obesity and elevated baseline transaminases.

Growth hormone deficiency and human immunodeficiency virus.

Treatment with highly active antiretroviral drugs (HAART) is associated with several endocrine and metabolic comorbidities. Pituitary growth hormone (GH) secretion seems to be altered in human immunodeficiency virus (HIV) infection, and about one-third of patients have biochemical GH deficiency (GHD). We undertake a historical review of the functioning of the GH/insulin-like growth factor-1 (IGF-1) axis in patients with acquired immunodeficiency syndrome, and provide an overview of the main changes of the GH/IGF-1 axis occurring today in patients with HIV. Both spontaneous GH secretion and GH response to provocative stimuli are reduced in patients with HIV infection, especially in those with HIV-related lipodystrophy. The role of fat accumulation on flattened GH secretion is discussed, together with all factors able to potentially interfere with the pituitary secretion of GH. Several factors contribute to the development of GHD, but the pathophysiologic mechanisms involved in the genesis of GHD are complex and not yet fully elucidated owing to the difficulty in separating the effects of HIV infection from those of HAART, comorbidities and body changes. An update on the putative mechanisms involved in the pathogenesis of altered GH secretion in these patients is provided, together with an overview on the therapeutic strategies targeting the GH/IGF-1 axis to counteract fat redistribution associated with HIV-related lipodystrophy. The clinical significance of GHD in the context of HIV infection is discussed. The administration of tesamorelin, a GH releasing hormone analogue, is effective in reducing visceral fat in HIV-infected patients with lipodystrophy. This treatment is promising and safer than treatment with high doses of recombinant human growth hormone, which has several side-effects.

Neuroprotective effect of epidermal growth factor plus growth hormone-releasing peptide-6 resembles hypothermia in experimental stroke.

BACKGROUND: Combined therapy with epidermal growth factor (EGF) and growth hormone-releasing peptide 6 (GHRP-6) in stroke models has accumulated evidence of neuroprotective effects from several studies, but needs further support before clinical translation. Comparing EGF + GHRP-6 to hypothermia, a gold neuroprotection standard, may contribute to this purpose. OBJECTIVES: The aims of this study were to compare the neuroprotective effects of a combined therapy based on EGF + GHRP-6 with hypothermia in animal models of (a) global ischemia representing myocardial infarction and (b) focal brain ischemia representing ischemic stroke. METHODS: (a) Global ischemia was induced in Mongolian gerbils by a 15-min occlusion of both carotid arteries, followed by reperfusion. (b) Focal brain ischemia was achieved by intracerebral injection of endothelin 1 in Wistar rats. In each experiment, three ischemic treatment groups - vehicle, EGF + GHRP-6, and hypothermia - were compared to each other and to a sham-operated control group. End points were survival, neurological scores, and infarct volume. RESULTS: (a) In global ischemia, neurological score at 48-72 h, infarct volume, and neuronal density of hippocampal CA1 zone in gerbils treated with EGF + GHRP-6 were similar to the hypothermia-treated group. (b) In focal ischemia, the neurologic score and infarct volume of rats receiving EGF + GHRP-6 were also similar to animals in the hypothermia group. DISCUSSION: With hypothermia being a good standard neuroprotectant reference, these results provide additional proof of principle for EGF and GHRP-6 co-administration as a potentially neuroprotective stroke therapy.

Predictors of Treatment Response to Tesamorelin, a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat.

BACKGROUND: Tesamorelin, a synthetic analog of human growth hormone-releasing factor, decreases visceral adipose tissue (VAT) in human immunodeficiency virus (HIV)-infected patients with lipodystrophy. OBJECTIVES: 1) To evaluate the utility of patient characteristics and validated disease-risk scores, namely indicator variables for the metabolic syndrome defined by the International Diabetes Federation (MetS-IDF) or the National Cholesterol Education Program (MetS-NCEP) and the Framingham Risk Score (FRS), as predictors of VAT reduction during tesamorelin therapy at 3 and 6 months, and 2) To explore the characteristics of patients who reached a threshold of VAT <140 cm2, a level associated with lower risk of adverse health outcomes, after 6 months of treatment with tesamorelin. METHODS: Data were analyzed from two Phase 3 studies in which HIV-infected patients with excess abdominal fat were randomized in a 2:1 ratio to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) subcutaneously daily for 6 months, using ANOVA and ANCOVA models. RESULTS: Metabolic syndrome (MetS-IDF or MetS-NCEP) and FRS were significantly associated with VAT at baseline. Presence of metabolic syndrome ([MetS-NCEP), triglyceride levels >1.7 mmol/L, and white race had a significant impact on likelihood of response to tesamorelin after 6 months of therapy (interaction p-values 0.054, 0.063, and 0.025, respectively). No predictive factors were identified at 3 months. The odds of a VAT reduction to <140 cm2 for subjects treated with tesamorelin was 3.9 times greater than that of subjects randomized to placebo after controlling for study, gender, baseline body mass index (BMI) and baseline VAT (95% confidence interval [CI] 2.03; 7.44). CONCLUSIONS: Individuals with baseline MetS-NCEP, elevated triglyceride levels, or white race were most likely to experience reductions in VAT after 6 months of tesamorelin treatment. The odds of response of VAT <140 cm2 was 3.9 times greater for tesamorelin-treated patients than that of patients receiving placebo.

Normativa SEPAR sobre disfunción muscular de los pacientes con enfermedad pulmonar obstructiva crónica / Guidelines for the evaluation and treatment of muscle dysfunction in patients with chronic obstructive pulmonary disease

La disfunción muscular de pacientes con enfermedad pulmonar obstructiva crónica (EPOC) constituye una de las comorbilidades más importantes, con repercusiones negativas en su capacidad de ejercicio y calidad de vida. En la presente normativa se ha resumido la literatura publicada más recientemente sobre los diferentes aspectos del tema y se ha utilizado también la escala Grading of Recommendations Assessment, Development, and Evaluation (GRADE) de recomendaciones sobre el grado de evidencia de las diferentes propuestas de la normativa. Respecto a una población control, se estima que en un tercio de los pacientes EPOC la fuerza del cuádriceps es un 25% inferior incluso en estadios precoces de su enfermedad. Aunque tanto los músculos respiratorios como los de las extremidades están alterados, estos últimos suelen verse mayormente afectados. Diversos factores y mecanismos biológicos están involucrados en la disfunción muscular de los pacientes. Se proponen diversas pruebas para evaluar y diagnosticar el grado de afectación de los músculos respiratorios y de las extremidades (periféricos), así como identificar la capacidad de esfuerzo de los pacientes (prueba de marcha de 6min y cicloergometría). Se describen también las posibles estrategias terapéuticas vigentes que incluyen las diversas modalidades de entrenamiento y de soporte farmacológico y nutricional.(AU)

In patients with chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction is a major comorbidity that negatively impacts their exercise capacity and quality of life. In the current guidelines, the most recent literature on the various aspects of COPD muscle dysfunction has been included. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) scale has been used to make evidence-based recommendations on the different features. Compared to a control population, one third of COPD patients exhibited a 25% decline in quadriceps muscle strength, even at early stages of their disease. Although both respiratory and limb muscles are altered, the latter are usually more severely affected. Numerous factors and biological mechanisms are involved in the etiology of COPD muscle dysfunction. Several tests are proposed in order to diagnose and evaluate the degree of muscle dysfunction of both respiratory and limb muscles (peripheral), as well as to identify the patients' exercise capacity (six-minute walking test and cycloergometry). Currently available therapeutic strategies including the different training modalities and pharmacological and nutritional support are also described.(AU)

Population pharmacokinetic and pharmacodynamic analysis of tesamorelin in HIV-infected patients and healthy subjects.

The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2 mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an "episodic" manner, i.e., for a finite duration of time. The resulting PK/PD model of GH was used to describe the time course of IGF-1. The effect of age, body weight, body mass index, sex, race, and health status on the model parameters was evaluated. The model was qualified using predictive checks and non-parametric bootstrap. Within the range of the values evaluated no covariates were significantly associated with GH or IGF-1 model parameters. Model evaluation procedures indicated accurate prediction of the selected pharmacodynamic markers. The time course of GH and IGF-1 concentrations following multiple doses of tesamorelin were well predicted by the sequential PK/PD model developed using Phase I data.

Growth hormone-releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy.

BACKGROUND: Growth hormone-releasing hormone agonists (GHRH-As) stimulate cardiac repair following myocardial infarction (MI) in rats through the activation of the GHRH signaling pathway within the heart. We tested the hypothesis that the administration of GHRH-As prevents ventricular remodeling in a swine subacute MI model. METHODS AND RESULTS: Twelve female Yorkshire swine (25 to 30 kg) underwent transient occlusion of the left anterior descending coronary artery (MI). Two weeks post MI, swine were randomized to receive injections of either 30 µg/kg GHRH-A (MR-409) (GHRH-A group; n=6) or vehicle (placebo group; n=6). Cardiac magnetic resonance imaging and pressure-volume loops were obtained at multiple time points. Infarct, border, and remote (noninfarcted) zones were assessed for GHRH receptor by immunohistochemistry. Four weeks of GHRH-A treatment resulted in reduced scar mass (GHRH-A: -21.9 ± 6.42%; P=0.02; placebo: 10.9 ± 5.88%; P=0.25; 2-way ANOVA; P=0.003), and scar size (percentage of left ventricular mass) (GHRH-A: -38.38 ± 4.63; P=0.0002; placebo: -14.56 ± 6.92; P=0.16; 2-way ANOVA; P=0.02). This was accompanied by improved diastolic strain. Unlike in rats, this reduced infarct size in swine was not accompanied by improved cardiac function as measured by serial hemodynamic pressure-volume analysis. GHRH receptors were abundant in cardiac tissue, with a greater density in the border zone of the GHRH-A group compared with the placebo group. CONCLUSIONS: Daily subcutaneous administration of GHRH-A is feasible and safe in a large animal model of subacute ischemic cardiomyopathy. Furthermore, GHRH-A therapy significantly reduced infarct size and improved diastolic strain, suggesting a local activation of the GHRH pathway leading to the reparative process.

Treatment of dyslipidemia in HIV.

Patients infected with HIV have a high risk of developing dyslipidemia. Effective therapeutic strategies can be challenging due to an increase risk of drug interactions and other comorbidities. Understanding the underlying pathophysiology and the principles of pharmacological and non-pharmacological therapeutic interventions can be of value in the appropriate management of dyslipidemia in the HIV-infected patient.

Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation.

Disruptions in immunity and occurrence of inflammation cause many eye diseases. The growth hormone-releasing hormone-growth hormone-insulin-like growth factor-1 (GHRH-GH-IGF1) axis exerts regulatory effects on the immune system. Its involvement in ocular inflammation remains to be investigated. Here we studied this signaling in endotoxin-induced uveitis (EIU) generated by LPS. The increase in GHRH receptor (GHRH-R) protein levels was parallel to the increase in mRNA levels of pituitary-specific transcription factor-1, GHRH-R splice variant 1, GHRH, and GH following LPS insult. Elevation of GHRH-R and GH receptor was localized on the epithelium of the iris and ciliary body, and GHRH-R was confined to the infiltrating macrophages and leukocytes in aqueous humor but not to those in stroma. Treatment with GHRH-R antagonist decreased LPS-stimulated surges of GH and IGF1 in aqueous humor and alleviated inflammation by reducing the infiltration of macrophages and leukocytes and the production of TNF-α, IL-1ß, and monocyte chemotactic protein-1. Our results indicate that inflammation in the iris and ciliary body involves the activation of GHRH signaling, which affects the recruitment of immune cells and the production of proinflammatory mediators that contribute to EIU pathogenesis. Moreover, the results suggest that GHRH-R antagonists are potential therapeutic agents for the treatment of acute ocular inflammation.

Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial.

IMPORTANCE: Among patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown. OBJECTIVE: To investigate the effect of tesamorelin on visceral and liver fat. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized, placebo-controlled trial conducted among 50 antiretroviral-treated HIV-infected men and women with abdominal fat accumulation at Massachusetts General Hospital in Boston. The first patient was enrolled on January 10, 2011; for the final patient, the 6-month study visit was completed on September 6, 2013. INTERVENTIONS: Participants were randomized to receive tesamorelin, 2 mg (n=28), or placebo (n=22), subcutaneously daily for 6 months. MAIN OUTCOMES AND MEASURES: Primary end points were changes in visceral adipose tissue and liver fat. Secondary end points included glucose levels and other metabolic end points. RESULTS: Forty-eight patients received treatment with study drug. Tesamorelin significantly reduced visceral adipose tissue (mean change, -34 cm2 [95% CI, -53 to -15 cm2] with tesamorelin vs 8 cm2 [95% CI, -14 to 30 cm2] with placebo; treatment effect, -42 cm2 [95% CI, -71 to -14 cm2]; P = .005) and liver fat (median change in lipid to water percentage, -2.0% [interquartile range {IQR}, -6.4% to 0.1%] with tesamorelin vs 0.9% [IQR, -0.6% to 3.7%] with placebo; P = .003) over 6 months, for a net treatment effect of -2.9% in lipid to water percentage. Fasting glucose increased in the tesamorelin group at 2 weeks (mean change, 9 mg/dL [95% CI, 5-13 mg/dL] vs 2 mg/dL [95% CI, -3 to 8 mg/dL] in the placebo group; treatment effect, 7 mg/dL [95% CI, 1-14 mg/dL]; P = .03), but changes at 6 months in fasting glucose (mean change, 4 mg/dL [95% CI, -2 to 10 mg/dL] with tesamorelin vs 2 mg/dL [95% CI, -4 to 7 mg/dL] with placebo; treatment effect, 2 mg/dL [95% CI, -6 to 10 mg/dL]; P = .72 overall across time points) and 2-hour glucose (mean change, -1 mg/dL [95% CI, -18 to 15 mg/dL] vs -8 mg/dL [95% CI, -24 to 8 mg/dL], respectively; treatment effect, 7 mg/dL [95% CI, -16 to 29 mg/dL]; P = .53 overall across time points) were not significant. CONCLUSIONS AND RELEVANCE: In this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and additionally with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01263717.

Therapies for musculoskeletal disease: can we treat two birds with one stone?

Musculoskeletal diseases are highly prevalent with staggering annual health care costs across the globe. The combined wasting of muscle (sarcopenia) and bone (osteoporosis)-both in normal aging and pathologic states-can lead to vastly compounded risk for fracture in patients. Until now, our therapeutic approach to the prevention of such fractures has focused solely on bone, but our increasing understanding of the interconnected biology of muscle and bone has begun to shift our treatment paradigm for musculoskeletal disease. Targeting pathways that centrally regulate both bone and muscle (eg, GH/IGF-1, sex steroids, etc.) and newly emerging pathways that might facilitate communication between these 2 tissues (eg, activin/myostatin) might allow a greater therapeutic benefit and/or previously unanticipated means by which to treat these frail patients and prevent fracture. In this review, we will discuss a number of therapies currently under development that aim to treat musculoskeletal disease in precisely such a holistic fashion.

The effects of tesamorelin on phosphocreatine recovery in obese subjects with reduced GH.

CONTEXT: Few studies have assessed the relationship between GH and mitochondrial function. OBJECTIVE: The objective of this study was to determine the effects of improving IGF-I using a GHRH analog, tesamorelin, on mitochondrial function assessed by phosphocreatine (PCr) recovery using (31)P magnetic resonance spectroscopy in obese adults with reduced GH. DESIGN: A total of 39 obese men and women with reduced GH secretion as determined by GHRH-arginine stimulation tests underwent magnetic resonance spectroscopy as part of a 12-month, double-blind, randomized, placebo-controlled trial comparing tesamorelin vs placebo. PCr recovery after submaximal exercise was assessed at baseline and at 12 months. RESULTS: At baseline, there were no differences in age, sex, race/ethnicity, and GH or PCr parameters between tesamorelin and placebo. After 12 months, tesamorelin treatment led to a significantly greater increase in IGF-I than did placebo treatment (change, 102.9±31.8 µg/L vs 22.8±8.9 µg/L, tesamorelin vs placebo; P=.02). We demonstrated a significant positive relationship between increases in IGF-I and improvements in PCr recovery represented as ViPCr (R=0.56; P=.01). The association between IGF-I and PCr recovery was even stronger among subjects treated with tesamorelin only (ViPCr: R=0.71; P=.03). This association remained significant after controlling for age, sex, race, ethnicity, and parameters of body composition and insulin sensitivity (all P<.05). CONCLUSIONS: Increases in IGF-I from 12 months of treatment with tesamorelin were significantly associated with improvements in PCr recovery parameters in obese men and women with reduced GH secretion, suggestive of improvements in mitochondrial function.